tbuckley/cabot-search huggingface dataset:
Evaluation of somatic and germline variants in patients with small bowel adenocarcinoma reveals clinically actionable targets.
Authors: Deng Wei, Si Liu, Xiaomo Li, Tonghui Ma
Journal: Journal of Clinical Oncology (2022)

4159 Background: Small bowel adenocarcinoma (SBA) is a rare gastrointestinal cancer with a poor prognosis and limited treatment options. Because the treatments for colorectal cancer showed limited efficacy in SBA, the NCCN guide strongly encourages SBA patients to participate in clinical trials. In this study, we aimed to explore clinically actionable variants in a large cohort of patients with SBA to assist oncologists to select the matched trials for patients. Methods: To explore therapeutic targets in 84 Chinese SBA patients, a deep sequencing panel (OncoPanscan, Genetron health) was used to characterize somatic alterations including point mutations, indels, copy number alterations, gene fusions as well as pathogenic germline variants. Results: Recurrent somatic mutations included TP53 (57%), KRAS (56%), APC (31%), SMAD4 (21%), MDM2 (13%), CTNNB1 (12%), KMT2C (12%), SOX9 (12%), ARID2 (12%), FAT3 (11%), FBXW7 (10%), SPTA1(10%) and PIK3CA (10%). Of the entire cohort, we observed five activating PIK3CA mutations (R108H; G364R; E542K; E545K, n = 2) which may be sensitive to FDA-approved PIK3CA inhibitor alpelisib. Additionally, patients with loss-of-function mutation in NF1 (n = 2), STK11 (n = 1) and PTEN (n = 1) can be targeted with MEK inhibitor selumetinib and mTOR inhibitor everolimus, respectively. Except for one V600E mutation, all mutations in BRAF are either type 2 (L597R, n = 1) or type 3 (N581S, n = 1; D594N, n = 4) which were sensitive to MEK inhibitor trametinib. We also found four type 2 MAP2K1 activating mutations (K57E, K57N, and F53L) which can be targeted by trametinib. Furthermore, oncogenic ERBB2/HER2 mutations were seen in 4 patients including S310F (n = 1), V842I (n = 2) and V777L (n = 1). We also found one patient harbored ERBB2/HER2 high magnification amplification. These five patients were candidates for HER2-targeted therapy clinical trials. Interestingly, one IDH1 mutation (R132C) carrier in our cohort might benefit from ivosidenib. In addition, we observed targetable gene amplification of MDM2 (n = 2) and FGF3/4/19 (n = 2). There were two patients with MLH1 loss-of-function germline mutations that may benefit from immunotherapy. Among 78 patients with available MSI status, three were designated as microsatellite instability. The median TMB of microsatellite stable patients was 2.82 mutations/Mb. Lastly, we observed five deleterious germline mutations, three for SBDS, one each for APC and ERCC5. Taken together, at least 33 (39%) patients in our cohort harbored actionable genetic alterations. Conclusions: Through comprehensive genomic characterization of Chinese SBA patients, we identified actionable variants of multiple signaling pathways in plenty. NGS profiling results can guide physicians to enroll a significant portion of SBA patients in genomically-matched clinical trials.
Immunotherapy plus chemotherapy versus chemotherapy alone as first-line treatment for non-small cell lung cancer: A systematic review and meta-analysis.
Authors: Basel Abdelazeem, Kirellos Said Abbas, Fatma Labieb, Abdul Karim Arida, Nahla Ahmed El-Shahat, Joseph Shehata, Emad Kandah, Bilal Malik, Maxwell Oluwole Akanbi, Abdul Rafae, Nayha Tahir, Ahsan Wahab, Hamid Ehsan
Journal: Journal of Clinical Oncology (2022)

e21092 Background: There is an emerging role of immunotherapy plus chemotherapy (ICC) in the front-line setting for the treatment of Non-Small Cell Lung Cancer (NSCLC) with reported improvement in overall survival (OS) and progression-free survival (PFS). In this review, we highlighted the efficacy and safety of combination regimens as a first-line therapy for NSCLC. Methods: A comprehensive literature search was done on PubMed, Cochrane, Embase, WOS, and Scopus until Dec-2021. The outcomes included progression free survival (PFS) and/or overall survival (OS) and treatment-related adverse events (TRAEs). The inverse variance method was used to generate hazard ratios (HR) with the corresponding 95% confidence intervals for the OS and PFS. Meanwhile, Mantle-Hazard variance was used to create risk ratios for TRAEs. Results: The total eleven randomized controlled trials (RCTs) involving 6,386 patients (pts) were included. 3,850 pts received ICC while 2536 pts received chemotherapy., Four studies each used atezolizumab and pembrolizumab while one study each used nivolumab, tislelizumab, and camrelizumab. The ICC group showed a significant improvement in both PFS (HR, 0.60; 95% CI, 0.54-0.66; p = &lt; 0.00001) and OS (HR, 0.77; 95% CI, 0.68-0.87; p = &lt; 0.0001). Atezolizumab combinations have better PFS and OS compared to the other combinations; HR 0.65 (0.59-0.71) and 0.82 (0.74-0.90), respectively. There was no statistically significant difference between the ICC and control groups regarding TRAEs (RR, 1.07; 95% CI, 0.99-1.16; p = 0.09). Further subgroup analysis is mentioned in the table. Conclusions: The ICC seems to be a promising front-line therapy for NSCLC with superior PFS and OS compared to chemotherapy alone and without significant increase in TRAES. [Table: see text]
The role and impact of immunotherapy in multiple malignancies in the Mexican population.
Authors: Juan Jose Juarez - Vignon Whaley, Gisela Sanchez Dominguez, Iván Romarico Gonzalez Espinoza, Lizbett Vanessa Garcia Montes, Jorge Alatorre-Alexander, Osvaldo Hernandez Flores, Julio Cesar Garibay Diaz, Jeronimo Rafael Rafael Rodriguez Cid
Journal: Journal of Clinical Oncology (2022)

e14570 Background: Cancer in Mexico represents the third cause of death nationally. Immunotherapy agents have changed management and prognosis of cancer patients. Immune-checkpoint agents are now being used as both first- and second-line treatment improving cancer patient prognosis, nevertheless it is not always accessible. Methods: Retrospective review of patients diagnosed with any type of cancer that received immunotherapy during their disease course from the last 5-years. We present the most common malignancies, immunotherapeutic regimens received, population characteristics and survival analysis. Results: 130 records of patients ≥18 years that received immunotherapy were included. 52.3% female with mean age of 59 years (range, 22-89 years), 48.5% former smokers (average pack/year of 22.5) and 31.5% asbestos exposure. 53.1% were ECOG 0 and 82.3% clinical stage IV. 62.3% of cases were lung adenocarcinoma, followed by lung epidermoid carcinoma (13.1%) and 10% small-cell lung carcinoma. Immunotherapeutic agents used included nivolumab in 63.1%, pembrolizumab 12.3%, nivolumab + ipilimumab 8.5%, durvalumab 6.2%, pembrolizumab + ipilimumab 4.6%. 36.2% of patients received immunotherapy as second line treatment, 30.0% as third and 23.8% as first line treatment. The best Response Evaluation Criteria in Solid Tumors (RECIST) was RECIST 3 in 46.2% followed by RECIST 0 with 25.4%. Median progression-free survival (PFS) was 5 months (95% CI; 3.883-6.117) and median OS of 13 months (95% CI; 10.210-15.790). Analysis per immunotherapy on PFS (p = 0.0414) and OS (p = 0.0046) demonstrated pembrolizumab had the longest median PFS with 19-months and OS with 22-months. Analysis between tumor types was significant for both PFS (p = 0.0018) and OS (p = 0.0090) with melanoma having the longest median PFS (42-months) and OS (46-months). Conclusions: Immunotherapy has changed cancer management; however, its use depends on specific biomarkers and adequate patient selection. Not all patients benefit from immunotherapy, in a country like ours where resources are limited, it is of vital importance to properly select candidates for immunotherapy. Even though, all patients had an FDA-approved indication at the time of receiving immunotherapy, PFS and OS are not as significant as Phase 3 studies demonstrate, this may be due to late stages, advanced ECOG, correct biomarkers availability and adequate patient selection. It is important to mention that about 40-60% of patients with immunotherapy do not respond adequately. In our study, because there is more evidence with pembrolizumab, the patients who received it were better chosen and therefore there was an impact in PFS and OS. Immunotherapy selection also depends on physician experience to the different immunotherapy regimens.
Estimating patient demand for oncologists in the United States using Google trends.
Authors: Shanawar Waris, Rahul Raiker, Nanda Siva, Monika Koirala, Haig Pakhchanian, Osama Boustany, Ahmed A. Khalid
Journal: Journal of Clinical Oncology (2022)

e18535 Background: Cancer accounts for a massive burden of global disease, healthcare expenditure, and is one of the leading causes of death worldwide, accounting for approximately 1 in 6 deaths. As both the incidence and prevalence of cancer continue to increase, along with the percentage of the population over the age of 65, it is important to understand patient demand for oncologists. Previous studies have predicted a shortage of over two thousand oncologists by 2025. The inconsistencies between supply and demand for oncologists require analysis and supervision to identify potential gaps in oncological care and fulfill patient demand for quality care. Methods: The average relative search volume (RSV) for the term “oncologist” was determined by analyzing Google Trends from 2004-2019 for each state. The oncologist per capita values were computed by taking the number of oncologists per state and then dividing by the corresponding 2019 Census estimates. The RSV values were then divided by per capita values to quantify demand index and standardized to generate a relative demand index (RDI). A spearman’s rho correlation test was also conducted to assess the relationship between RDI and overall 2019 state health rankings as conducted by the America’s Health Rankings group. Results: The states with highest RSV was New Jersey (100), Florida/Tennessee (98), and Connecticut (97), while the lowest RSV were Oregon (53), Alaska (44), and Vermont (41). The RDI for oncologists was greatest in Idaho (100), Mississippi (86), and Arkansas (77) while the lowest were for Vermont (15), Massachusetts (14), and District of Columbia (8). Spearman’s rho test revealed a strong negative relationship between RDI and overall state health ranking that was statistically significant (r s = -0.6363, p &lt; 0.001). Conclusions: These trends may give us a preliminary idea of states that have unmet healthcare needs in oncology. Further studies are warranted.
Monitoring efficacy of neoadjuvant sunitinib in metastatic renal cell carcinoma using a personalized and tumor informed ctDNA assay.
Authors: Christine B. Peterson, Ekaterina Kalashnikova, Jordan Feeney, Allyson Koyen Malashevich, Himanshu Sethi, Alexey Aleshin, Eric Jonasch
Journal: Journal of Clinical Oncology (2022)

4525 Background: Approximately 30% of renal cell carcinoma (RCC) cases present as stage IV at the time of diagnosis. Metastatic RCC (mRCC) is associated with poor outcomes, with a five-year survival rate below 50%. Tools to evaluate the efficacy of novel systemic regimens are needed. Biomarkers like ctDNA can accurately and non-invasively assess molecular residual disease (MRD) in response to therapy and monitor disease status over time to predict disease progression. Here, we aimed to determine the feasibility of performing personalized and tumor-informed ctDNA testing in mRCC patients enrolled on a study integrating systemic therapy with surgical cytoreduction, as well as to measure patient response to sunitinib by assessing ctDNA dynamics. Methods: We analyzed a cohort of 21 mRCC patients with median age of 59.5 (43-76) years who were treated with sunitinib, and had planned cytoreductive nephrectomy during their second cycle of therapy. Baseline and post-first cycle ctDNA levels were measured using a personalized and tumor-informed ctDNA assay (SignateraTM bespoke mPCR NGS assay). Changes in ctDNA levels from baseline to the best response time point were correlated with disease status as assessed by radiological imaging. Results: In this cohort, baseline ctDNA was detected in 81% (17/21) of patients, with higher ctDNA concentrations observed in patients who presented with multiple distant metastases (n = 11) compared to the 10 cases with a single metastatic mass (median 5.8 vs 1.3 mean tumor molecules/mL, not statistically significant). Of those with baseline ctDNA measurement, 12% (2/17) cleared their ctDNA, 24% (4/17) had a decrease in ctDNA, and 59% (10/17) had an increase in ctDNA after 4 weeks of sunitinib. During the course of treatment, patients whose ctDNA concentration increased from baseline were more likely to experience a disease progression (HR: 3.9 95% CI 1.13-13.7; p = 0.032) compared to those whose ctDNA decreased. In addition, higher ctDNA concentration before surgery after initial treatment with sunitinib correlated with shorter time to progression (p = 0.04). Conclusions: Our results demonstrate the feasibility and prognostic value of personalized and tumor-informed ctDNA testing for determining response to systemic therapy in patients with mRCC. Early signs of unfavorable ctDNA kinetics can provide rationale for modification of systemic therapy in order to enhance response. Future work exploring the clinical utility of ctDNA testing in larger mRCC cohorts is warranted.
Efficacy of the novel treatments of BCC with bone metastasis.
Authors: Mohammad Ali Esmaeil Pour, Mahsa Mohebtash, Ali Amin, Azadeh Khayyat, Amir-Reza Khalili-Toosi, Seyedreza Mousavi, Mengni Guo, Jieying Liu
Journal: Journal of Clinical Oncology (2022)

e14547 Background: Eighty percent of nonmelanoma skin malignancies are basal cell carcinomas (BCC). Metastasis in BCC is about 0.0028 to 0.55. Diagnosis and treatment of metastatic BCC is challenging due to its rarity. In approximately 85% of metastatic BCC, the most common metastatic organs are lymph nodes. Methods: We reviewed 31 skin BCCs with bone metastasis in the past 60 years and 10 observation studies on the efficacy of Sonic hedgehog inhibitors (SHHis). We focused on treatment and outcome of 31 metastatic BCC. Results: The main treatment option was surgery and radiotherapy is a palliative option. Among chemotherapeutic and immunotherapeutic agents, SHHis (e.g. vismodegib and sonidegib) appear to be effective, with reported ORR of 43-100%, and CRR range of 3%-54%. In locally advanced BCCs, vismodegib shows 10 times higher CRRs compared to sonidegib, although ORRs were similar. In metastatic BCC, overall response to vismodegib was three times higher. The common adverse effects of SHHis limit their administration. Conclusions: BCC is a common skin neoplasm that rarely demonstrates metastasis. Among the chemotherapy agents administered, vismodegib appears promising.[Table: see text]
Early together: A randomized phase III study of early palliative care in metastatic uveal melanoma (MUM).
Authors: Sophie Piperno-Neumann, Manuel Rodrigues, Timothee Marchal, Lauris Gastaud, Anne Fogliarini, Carole Bouleuc, Yves Libert, Leanne de Koning, Anne Bredart, Alexia Savignoni, Sylvie Dolbeault, Alexis Burnod
Journal: Journal of Clinical Oncology (2022)

TPS9598 Background: Uveal melanoma is a rare cancer. Up to 50% of patients (pts) develop metastasis, mainly hepatic. Overall survival in metastatic pts is 12 months (mo), contrasting with a good overall condition until death. To evaluate the impact of integrating early palliative care on patient needs and self-efficacy, we designed a comparative randomized trial in MUM pts. Methods: 162 pts will be randomized (1:2) between the control and the experimental groups in two French centres (Institut Curie-Paris and Centre Antoine Lacassagne-Nice). In the control group, palliative care is introduced according to international guidelines. In the experimental group, it is added earlier, concomitant to the announcement of metastases by the medical oncologist. The main objective is to assess if early supportive care impacts on patient psychological needs at 6 mo, versus standard of care, based on the SCNS-SF34 questionnaire. Secondary objectives include patient’s other needs at 6 and 12 mo, quality of life (QLQ-C30), progression-free and overall survival, and partners’ needs (SCNS-P&amp;C). MUM pts, suitable for a treatment with no curative intent, ECOG PS 0-1, with no physical or biological sign of disease, and capable of filling questionnaires are eligible. Questionnaires are completed by all pts at each oncological visit (baseline, 3, 6, 9 and 12 mo). Supportive care visits take place every 6 weeks if needed and address patient’s information needs, disease and treatment understanding, social and psychological status, symptoms, and partners’ involvement. Prognostic uncertainty and disease seriousness in the absence of symptom is addressed depending on pts’ expressed needs. Medical oncologists and supportive care physicians from both centres attend communication skill training provided by an expert during the study. Analyses: SCNS-SF34 psychological needs scale scores at 6-mo will be compared with a Student’s t-test, in an ITT analysis. For 10 points mean score difference expected between groups (within standard deviation of 20 points) and a two-sided type 1 error of 5%, inclusion of 54 pts (control group) and 108 pts (experimental group) provides the study 85% of power. The planned inclusion period is 3 years, pts will be followed for one year, for a total study duration of 4 years. From July 2020 to January 2022, 63 pts have been enrolled in the trial; 2 pts declined. Five pts were removed early from the study: one for consent retrieval, 4 for early death due to metastasis. COVID-19 delayed enrollment for 5 months. We plan to complete the study Q4 2023 and to analyze the data Q4 2024. Clinical trial information: NCT04728113. [Table: see text]
Phase 1/2 dose escalation study of NUV-422, a potent inhibitor of cyclin-dependent kinases 2, 4, and 6, in recurrent or refractory (r/r) high-grade gliomas (HGG) and solid tumors.
Authors: Patrick Y. Wen, Jordi Rodon Ahnert, John D. Powderly, Howard Colman, Shannon L. Matheny, Anthony A. Golsorkhi, Teeru Bihani, Yan Zhang, Thomas Joseph Kaley
Journal: Journal of Clinical Oncology (2022)

TPS3173 Background: CDKs that govern the G1-S transition of the cell cycle (CDK2, CDK4 and CDK6) are deregulated in many cancers. CDK2 expression, in particular, is associated with worse overall survival in glioblastoma (GB), disease-free recurrence in prostate cancer, and resistance to approved CDK4/6 inhibitors (CDK4/6i) in breast cancer. These provide rationale for inhibition of CDK2/4/6 as a potential novel therapeutic strategy in these cancers. NUV-422 is a potent (low nM) small molecule CDK2/4/6i with limited activity against CDK1, a target potentially associated with toxicities in other CDKi. Preclinical studies have shown that NUV-422 has favorable blood-brain barrier penetration, inhibited growth of multiple glioma cell lines in vitro, and exhibited antitumor activity in GB xenograft models. NUV-422 also exhibited antitumor activity in multiple patient-derived xenograft (PDX) models of HR+ HER2- mBC resistant to CDK4/6i, and PDX models of prostate cancer resistant to anti-androgens. Methods: NUV-422-02 (NCT04541225) is a phase 1/2, first in human, open label, multicenter study to evaluate single-agent NUV-422 (given orally) in patients with advanced solid tumors (r/r HGG, r/r HR+ HER2- mBC, or r/r mCRPC). The Ph 1 dose escalation will use a 3+3 design to evaluate safety, tolerability, and PK of NUV-422 and establish the recommended phase 2 dose (RP2D). Ph 1 also includes a randomized surgical substudy to characterize PK and pharmacodynamics (PD) of preoperative NUV-422 in resected GB tumor tissue. After the RP2D is identified, parallel enrollment into phase 2 expansion cohorts will begin. Cohort 1 will evaluate isocitrate dehydrogenase wild type (IDH-WT) GB. Cohort 2 will evaluate HR+ HER2- mBC (without active brain metastases); Cohort 3 will evaluate mCRPC; and Cohort 4 will evaluate HR+ HER2- mBC with active brain metastases. The Ph 2 primary endpoint is objective response rate. Secondary efficacy endpoints include clinical benefit rate, duration of response, progression-free survival, and overall survival. Response assessments will be based on response criteria appropriate to the tumor type (HGG [RANO]; HR+HER2- mBC [RECIST 1.1 or RANO-Brain Metastases]; mCRPC [RECIST 1.1, PCWG3, prostate-specific antigen decrease]). Blood, urine, or tumor tissue will be obtained to assess safety, PK, PD, and for additional exploratory analyses to characterize NUV-422 mechanism of action. Enrollment was initiated in December 2020, and dose escalation is ongoing. The NUV-422 program will also be expanded in 2022 to include additional studies in mBC and mCRPC in combination with standard of care treatments. Clinical trial information: NCT04541225.
Validation of a multi-modal blood-based test for the detection of colorectal cancer with sub single molecule sensitivity.
Authors: Kevin D'Auria, Yunpei Chang, Michael Multhaup, Haley Axelrod, Lu Zheng, Jordan Burke, William Young Greenwald, Yupeng He, Kathryn Pendleton, Nathan McDonald, Victoria M. Raymond, Anna Hartwig, Sven Duenwald, Darya Chudova, AmirAli Talasaz
Journal: Journal of Clinical Oncology (2022)

3627 Background: Blood-based colorectal cancer (CRC) screening tests can improve adherence to screening guidelines. Yet, current commercially available options have poor sensitivity and specificity inhibiting incorporation into routine clinical care. Here we report the validation of a blood-based test for the detection of colorectal cancer and advanced neoplasia. Methods: This blood-based test aims to detect colorectal neoplasia by identifying tumor-associated biomarkers including genomic or epigenomic (methylation and fragmentomics) signatures in cell-free DNA (cfDNA). cfDNA is partitioned based on methylation level, enriched for informative genomic regions, and sequenced. This novel workflow enables high-fidelity analysis of multi-modal information in majority of extracted cfDNA molecules. Results are integrated into a binary “detected” versus “not-detected” result using a proprietary bioinformatic pipeline (Guardant Health, USA). The assay was trained on samples obtained from &gt;6,000 unique individuals (2,685 cancer-free and 1,698 with advanced colorectal neoplasia (ACN) for training, 1,072 cancer-free and 551 with ACN for threshold setting). The thresholds were frozen prior to validation targeting a specificity of &gt; 91.5%. Each aspect of the validation study followed Nex-StoCT CLIA working group and CLSI guidelines. Results: Limit of detection (LoD) was established across six dilutions. Even for low cfDNA mass inputs of less than 4ng, the 95% LoD was determined to be less than 1 tumor-derived genomic equivalent (0.5), indicating over at least 10-fold increase in assay sensitivity compared to best-in-class assays for somatic mutation detection. Precision studies in 60 positive and negative replicates from clinical samples yielded &gt;90% average positive and negative percent agreement both within and between batches. Endogenous interference studies yielded &gt; 90% positive and negative percent agreement between reference control and common endogenous substances, including albumin, bilirubin, hemoglobin, triglycerides, and genomic DNA, in clinical positive and negative samples and minimally manipulated samples. The clinical validation of the test was conducted in &gt; 300 cases (biobanked pre-operative cohort for CRC cases and screening cohort for advanced adenoma and negative cases). Conclusions: Here we present the validation of a multi-modal blood-based test for the detection of colorectal cancer. This test is currently being evaluated in a registrational study (ECLIPSE: NCT04136002).